Abstract A key challenge in neuroscience is the development of methods to non-invasively manipulate specific neuronal cell types in vivo. While recent opto-, chemo- and magneto-genetic approaches have revolutionized our ability to control both neuronal and non-neuronal cell types, they each suffer from critical drawbacks, including the inability to deliver light to targets deep within the brain or to large volumes of the brain (opto-), and the lack of precise temporal control for both chemo- and magneto-genetic approaches. The Chalasani lab has recently demonstrated a noninvasive method for controlling the activity of neurons using ultrasound, a system they call sonogenetics. They have demonstrated that mechanosensitive TRP-N channel homologs from C. elegans, Hydractinia, and Hydra magnipapillata can be used to non-invasively activate mammalian cells both in vitro and in vivo. They hypothesize that target cells expressing these TRP-N channels are rendered sensitive to mechanical deformations generated by non-invasive ultrasound waves. This proposal aims to extend the sonogenetic approach to control specific neuronal populations throughout large volumes of the mouse brain, a system that would be useful for reversing electrophysiological and behavioral deficits seen in epilepsy, for example. They will identify channels with non-overlapping ultrasound stimulus ranges by testing variants and chimeras of the Hydra TRP-N channels in high-throughput imaging and slice culture electrophysiology assays in vitro, as well as in feeding and electromyography assays in vivo (Aim 1). They also plan to develop a new lithium niobate-based transducer that will deliver ultrasound throughout the mouse brain. Specifically, they will use Schroeder?s optimal diffuser design in a device that will generate spatiotemporally incoherent ultrasound that upon reflection, avoids interference and localized spikes in ultrasound (Aim 2). Finally, they plan to activate GABAergic inhibitory interneurons broadly throughout the brain to alleviate behavioral and electrophysiological deficits in mouse models of epilepsy and Rhett?s syndrome. Optogenetic, chemogenetic, and pharmacological methods have been previously used to control these cell populations, providing benchmarks for comparison. These studies will develop a noninvasive method for manipulating the activity of specific cells within large volumes of the rodent brain or body. Further, these methods can be translated into the human system to target specific cell populations for therapeutic purposes.